crossing96/oncoscreening huggingface dataset:
Prolonged Progression-Free Survival, Disease-Free Survival, and Cystectomy Avoidance With IL-15 Receptor Lymphocyte-Stimulating Agent NAI Plus Bacillus Calmette-Guérin in Bacillus Calmette-Guérin-Unresponsive Papillary-Only Nonmuscle-Invasive Bladder Cancer.	PURPOSE: In QUILT-3.032, the efficacy of interleukin-15 receptor agonist, nogapendekin alfa inbakicept (NAI), in combination with bacillus Calmette-Guérin (BCG) for BCG-unresponsive high-grade papillary-only nonmuscle-invasive bladder cancer was assessed. In this study, we report the 36-month follow-up among participants with BCG-unresponsive papillary disease (cohort B). MATERIALS AND METHODS: NCT03022825 is an open-label, multicenter study of patients with BCG-unresponsive high-grade Ta/T1 papillary nonmuscle-invasive bladder cancer who received 400 μg NAI plus 50 mg BCG intravesically weekly for 6 consecutive weeks. The primary end point is disease-free survival (DFS) at 12 months. Progression-free survival (PFS), disease-specific survival (DSS), and cystectomy avoidance were assessed. Treatment-related adverse events were assessed. RESULTS: At July 15, 2024, data cutoff, the DFS rates at 12, 24, and 36 months were 58.2% (95% CI: 46.6, 68.2), 52.1% (95% CI: 40.3, 62.7), and 38.2% (95% CI: 25.6, 50.6), respectively. The PFS rates at 12 and 36 months were 94.9% (95% CI: 86.9, 98.0) and 83.1% (95% CI: 69.5, 91.0). The DSS rates at 12 and 36 months were 98.7% (95% CI: 91.4, 99.8) and 96.0% (95% CI: 88.2, 98.7). The median DSS has not been reached. Cystectomy avoidance rates at 12 and 36 months were 92.2% (95% CI: 83.4, 96.4) and 81.8% (95% CI: 68.1, 90.1), with median time to cystectomy not reached. Most treatment-related adverse events were grade 1 to 2 (61%) with 3% grade 3 and no grade 4 to 5. CONCLUSIONS: The 12-month and 36-month DFS, PFS, DSS, and cystectomy avoidance rates demonstrate the effectiveness and safety of NAI plus BCG in the management of BCG-unresponsive papillary disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03022825.	bladder
Glutamine metabolism reprogramming promotes bladder cancer progression via PYCR1: a multi-omics and functional validation study.	BACKGROUND: Bladder cancer (BLCA) is a prevalent malignancy worldwide, with advanced stages linked to poor prognosis. Although immune checkpoint inhibitors (ICIs) show clinical promise in treating both operable and advanced BLCA, predicting patient responses remains a major challenge. Glutamine metabolism, a key aspect of metabolic reprogramming, has been implicated in tumor progression and immune modulation. However, the exact role of glutamine metabolism in BLCA remains poorly understood. This study aims to explore its association with clinical outcomes and immunotherapy response while functionally validating key regulatory genes. METHODS: An integrated approach combining targeted metabolomics, single-cell RNA sequencing, and bulk transcriptomic data was used to profile glutamine metabolism in BLCA comprehensively and identify potential metabolic biomarkers. A prognostic model, termed GMscore, based on glutamine metabolism, was constructed using principal component analysis (PCA). Key regulatory genes were identified through random forest analysis. Functional assays, including in vitro proliferation, migration, and metabolic assays, as well as in vivo xenograft models, were employed to validate the findings. RESULTS: Targeted metabolomics revealed increased glutamine metabolism in BLCA cell lines. The GMscore model, developed and validated across multiple cohorts, accurately predicted patient survival. In two immunotherapy cohorts (IMvigor210 and GSE91061), a lower GMscore correlated with improved therapeutic response, suggesting its potential as a predictive biomarker for immunotherapy efficacy. PYCR1 was identified as a key regulatory gene, exhibiting high expression in epithelial cells and cancer-associated fibroblasts (CAFs). Functional assays demonstrated that PYCR1 knockdown inhibited cell proliferation and migration and suppressed tumor growth in vivo. Mechanistically, PYCR1 facilitated proline synthesis through P5CS and activated the PI3K/AKT/mTOR signaling pathway, which modulated glutamine utilization and metabolic reprogramming in BLCA. CONCLUSIONS: This study provides a comprehensive analysis of glutamine metabolism in BLCA and introduces a clinically relevant prognostic model. PYCR1 was identified as a central metabolic regulator, underscoring its critical role in tumor development and progression.	bladder
Molecular Heterogeneity and Clinicopathologic Correlations in Inflammatory Myofibroblastic Tumors of the Urinary Bladder: A Study of 20 Cases With Predominant FN1::ALK Fusions and Novel Kinase Rearrangements.	Inflammatory myofibroblastic tumors (IMTs) of the urinary bladder are rare mesenchymal neoplasms with an incompletely defined molecular spectrum. This integrated clinicopathologic and molecular study of 20 bladder IMTs utilized immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and targeted RNA sequencing to characterize their molecular drivers. Clinically, patients (mean age 45 y) presented with hematuria (85%) and cystoscopic polypoid/nodular masses; despite muscularis propria invovlement (55%) or perivesical soft tissue extension (5%), clinical outcomes were excellent (90% disease-free survival; mean follow-up 32.6 mo), with 2 recurrences managed by repeat resection. Histologically, the tumors exhibited mixed growth patterns: compact spindle cell (75%), myxoid (50%), and hypocellular fibrous (20%), with 45% showing combined features. IHC revealed ALK positivity in 90% (18/20) of cases, predominantly diffuse cytoplasmic staining (17/18), while keratins (AE1/AE3 and/or CAM5.2) were positive in 83.3%. Molecular analysis identified ALK rearrangements in 87.5% (14/16) of FISH-tested cases (signal separation: 13% to 42%) and gene fusions in 88.9% (16/18) of RNA-sequenced cases, with FN1::ALK being the predominant fusion (75%, 12/16). Rare fusions included VCL::ALK , DCTN1::ALK , PPFIBP1::ALK , and a novel TFG::ROS1 (confirmed by RT-PCR and Sanger sequencing). Distinct genotype-phenotype correlations emerged: myxoid morphology strongly associated with FN1::ALK (87.5%, 7/8), while hypocellular fibrous patterns enriched non- FN1 fusions (75%, 3/4). The predominance of FN1::ALK fusions, sharing identical breakpoints ( ALK exons 18 to 19) with pseudosarcomatous myofibroblastic proliferations of the urinary bladder, alongside expanded molecular diversity (non- FN1/ROS1 fusions), supports their classification as a biological continuum of ALK -driven bladder mesenchymal neoplasms. These findings broaden the molecular genetic spectrum of bladder IMTs and advocate for histology-guided molecular testing to identify kinase fusions, reinforcing conservative management for these typically indolent tumors.	bladder
Non-invasive bladder cancer detection: Identification of a urinary volatile biomarker panel using GC-MS metabolomics and machine learning.	Early detection of bladder cancer (BC) remains a major clinical challenge due to the limitations of current diagnostic methods, which are often invasive, expensive, or insufficiently sensitive, particularly for early-stage disease. Metabolomics approaches, when integrated with machine learning (ML) techniques, offer a powerful platform for identifying novel, non-invasive biomarkers. In this study, urinary volatile organic compounds (VOCs) were analysed from 87 BC patients and 90 age- and sex-matched cancer-free controls using headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry (HS-SPME/GC-MS). Of the 90 VOCs identified, 27 were selected and used to train five ML algorithms-random forest (RF), support vector machine (SVM), partial least squares-discriminant analysis (PLS-DA), extreme gradient boosting (XGBoost), and k-nearest neighbors (k-NN). Model performance was evaluated using cross-validation and an independent validation set, with metrics including area under the curve (AUC), sensitivity, specificity, and accuracy. RF achieved the highest performance using all 27 features (AUC = 0.913; sensitivity, specificity, and accuracy = 85 %). After feature selection, an eight-VOC panel improved performance on the validation set (AUC = 0.872; sensitivity = 89 %, specificity = 92 %, accuracy = 91 %). The panel included ketones, aldehydes, a short fatty alcohol, and a phenol compound-seven elevated in BC, and one (acetone) decreased. This panel outperformed FDA-approved urinary assays and closely matched the specificity of urine cytology. These findings underscore the promise of VOC-based urinary biomarkers, in combination with ML, for the non-invasive detection of BC. Further large-scale validation studies are essential to confirm diagnostic utility and enable clinical translation.	bladder
Avelumab Maintenance Therapy in Patients With Curatively Unresectable Urothelial Carcinoma in Japan: Subgroup Analyses of Post-Marketing Surveillance Data by Age, Prior Chemotherapy Regimen, and Best Overall Response to Prior Chemotherapy.	INTRODUCTION: Avelumab maintenance therapy was approved in Japan for curatively unresectable urothelial carcinoma (UC) without progression after prior platinum-based chemotherapy (PBC) based on results from the JAVELIN Bladder 100 phase 3 trial. We report post hoc analyses of post-marketing surveillance (PMS) data in subgroups defined by age, prior PBC regimen, and best overall response (BOR) to prior PBC. METHODS: Patients with curatively unresectable UC who received ≥ 1 dose of avelumab maintenance in Japan between February and December 2021 were evaluated. The primary objective was to evaluate safety based on prespecified adverse drug reactions (ADRs). The secondary objective was to evaluate effectiveness, including time to treatment failure (TTF; discontinuation for any reason) and overall survival (OS). RESULTS: The analysis population included 453 patients. In patients aged ≤ 64 (n = 75), 65 to 74 (n = 198), or ≥ 75 (n = 180) years, prespecified ADRs occurred in 17 (22.7%), 69 (34.9%), and 58 (32.2%); median TTF was 4.8, 4.4, and 4.9 months; and 12-month OS rates were 77.6%, 82.7%, and 72.6%, respectively. In patients with prior cisplatin + gemcitabine (n = 267), carboplatin + gemcitabine (n = 163), or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (n = 9) treatment, prespecified ADRs occurred in 93 (34.8%), 45 (27.6%), and 3 (33.3%); median TTF was 4.6, 4.6, and 5.1 months; and 12-month OS rates were 79.6%, 73.8%, and 88.9%, respectively. In patients with prior complete response (n = 47), partial response (n = 242), or stable disease (n = 149), prespecified ADRs occurred in 16 (34.0%), 79 (32.6%), and 45 (30.2%); median TTF was 5.2, 4.6, and 4.6 months; and 12-month OS rates were 89.4%, 76.3%, and 75.8%, respectively. DISCUSSION: In this PMS population, safety and effectiveness were observed with avelumab maintenance therapy across subgroups defined by age, prior PBC regimen, or BOR to prior PBC. Findings support the favorable benefit-risk profile of avelumab maintenance in clinical practice. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR: UMIN 43435).	bladder
Addressing Uneven Treatment Discontinuation Rate in the Chemotherapy Arm of the EV-302 Phase 3 Randomized Clinical Trial: Implications for Outcome Interpretation.	INTRODUCTION: The EV-302 trial demonstrated a very significant overall survival (OS) benefit for Enfortumab Vedotin plus Pembrolizumab (EVP) relative to standard chemotherapy (CHT) for patients with metastatic urothelial carcinoma. However, questions have been raised regarding the high rate of treatment discontinuation in the CHT arm for reasons unrelated to adverse events or progression (33% vs. 10% with EVP, P < .01), potentially resulting in loss of unaccounted information, or informative censoring, and affecting survival results interpretation. MATERIALS AND METHODS: We performed a multistep analysis to assess the impact of differential dropout on trial outcomes. First, Kaplan-Meier (KM) curves were reconstructed from published data to estimate time-to-event outcomes. Second, a reverse KM analysis was conducted to evaluate censoring patterns in the overall population and key subgroups (PD-L1 expression; cisplatin eligibility). Third, simulation models were employed to test whether informative censoring could negatively impact survival benefit by EVP. Finally, we compared the CHT arm of EV-302 to those of other contemporary RCTs through reconstructed survival analyses and risk-of-bias assessments. RESULTS: Overall, no significant imbalance in censoring between the treatment arms of EV-302 was found on reverse KM analysis when assessing OS (P = .73); however, a significant difference was noted for progression-free survival (PFS) (P = .002). Simulation analysis revealed that even under extreme assumptions of informative censoring, the OS benefit of EVP remained statistically significant. Comparison with historical RCTs confirmed that the CHT outcomes in EV-302 were not anomalously poor. Risk of bias was low overall, although deviations from intervention and outcome measurement were flagged for EV-302. CONCLUSIONS: Despite the high discontinuation rate in the CHT arm, OS benefit with EVP remains robust. These findings support the reliability of EV-302 results and mitigate concerns about informative censoring, thus encouraging the use of EVP in clinical practice.	bladder
Oncolytic virus therapy for nonmuscle-invasive bladder cancer: current status and future directions.	PURPOSE OF REVIEW: Nonmuscle-invasive bladder cancer (NMIBC) patients with BCG-unresponsive disease have limited treatment options beyond radical cystectomy. With ongoing BCG shortages and the urgent need for bladder-preserving alternatives, this review examines the emerging role of oncolytic virus therapy as a novel intravesical treatment approach for this challenging patient population. RECENT FINDINGS: Multiple oncolytic viral platforms have entered clinical trials for NMIBC treatment, demonstrating promising efficacy and safety profiles. Cretostimogene grenadenorepvec has shown exceptional results in a phase 3 trial, achieving 74.5% complete response rates with durable responses exceeding 27 months in BCG-unresponsive carcinoma in situ. Combination therapy with pembrolizumab further enhanced efficacy, with a 57.1% complete response rate at 12 months and no progression to muscle-invasive disease. Other viral platforms, including herpes simplex, coxsackie, and measles viruses, have demonstrated preliminary antitumor activity with favorable safety profiles. These agents utilize three mechanisms of action: selective viral replication, direct oncolysis, and immune system activation. SUMMARY: Oncolytic virus therapy represents a paradigm shift toward an effective bladder-preserving treatment for BCG-unresponsive NMIBC. With phase 3 data supporting regulatory approval pathways, these therapies are poised to become new standards of care, offering hope for improved outcomes while avoiding radical surgery.	bladder
Metformin as an anti-cancer agent against bladder cancer acts via PD-L1 downregulation in an orthotopic mouse model.	BACKGROUND: PD-L1 is a crucial immune checkpoint protein that limits the effectiveness of antitumor immunity. Blocking the PD-L1/PD-1 pathway has shown promise in cancer treatment, but low response rates to checkpoint inhibitors highlight the need for alternative therapeutic strategies. Metformin, a drug primarily used for diabetes, has gained attention as a potential cancer treatment due to its effects on PD-L1 expression, the tumor microenvironment, and its ability to inhibit the proliferation of tumor cells. Meta-analyses suggest that metformin may reduce the incidence and improve the prognosis of bladder cancer in patients with type 2 diabetes, but the exact mechanisms by which it exerts its effects remain unclear. MATERIALS: This study employed a syngeneic orthotopic bladder cancer model with immunocompetent C57BL/6 mice to evaluate metformin's therapeutic effects. Safe dosage was established through a maximum tolerated dose (MTD) test, identifying 150 mg/kg/day as suitable. Tumor size, body weight, survival, and PD-L1 expression were measured, while a tetrazolium-based assay assessed bladder cancer cell proliferation in vitro. RESULTS: Findings revealed elevated PD-L1 gene and protein expression in mouse bladder cancer tissues. In vitro, metformin inhibited PD-L1 expression and proliferation of MB49 mouse bladder cancer cells. In vivo, metformin reduced cancer cachexia, tumor size, and improved survival at 150 mg/kg/day. Importantly, metformin attenuated tumor-induced PD-L1 upregulation in a dose-dependent manner. CONCLUSION: Overall, this study suggests that bladder tumors can increase PD-L1 expression to promote PD-L1-mediated intrinsic tumor growth pathways, and metformin effectively downregulates PD-L1 expression, suppresses bladder cancer cell proliferation, and prolongs survival in an orthotopic bladder cancer mouse model.	bladder
Intravesical recurrence after therapeutic ureteroscopy for upper tract urothelial carcinoma: a meta-analysis.	OBJECTIVE: To assess the role of ureteroscopy (URS) with laser ablation on oncological outcomes, namely, intravesical recurrence (IVR) rate, radical nephroureterectomy (RNU)-to-treat ratio and overall survival (OS), in patients with upper tract urothelial carcinoma (UTUC), an area of study that has been insufficiently addressed in the literature. MATERIALS AND METHODS: A systematic search (PROSPERO: CRD42025642480) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. A pooled analysis was performed to quantify the effect size (ES) for IVR rate, radical nephroureterectomy (RNU)-to-treat ratio and OS. Subgroup analyses were performed to evaluate patients who received postoperative instillations and to compare URS with laser ablation to RNU. RESULTS: Overall, 24 studies involving 1904 patients were included in the final analysis. The overall rate of IVR was 23.7% (n = 453). The overall pooled analysis showed an ES for IVR of 0.33, for RNU-to-treat ratio of 0.23, and for OS of 0.62 (all P ≤ 0.005). In the comparison between URS and RNU, the pooled ES of URS for IVR was 1.14 and for OS it was 1.43 (all P > 0.05). Within the subgroup analysis of patients who received postoperative instillations, the pooled ES for IVR was 0.38 (P = 0.029) and for RNU-to-treat ratio it was 0.25 (P = 0.012). CONCLUSIONS: In this systematic review, URS with laser ablation was found to exert a negligible effect on IVR rate. Moreover, no statistically significant differences in IVR nor in OS were recorded when URS was compared to RNU. URS can be performed without compromising the oncological outcomes of patients with UTUC.	bladder
Microbiome Shifts in Bladder Cancer: A Narrative Review of Urobiome Composition, Progression, and Therapeutic Impact.	Background/Objectives: Bladder cancer is a common malignancy with a high rate of recurrence and progression. Recent studies have identified that the urinary microbiome can be a key factor in tumor pathogenesis, progression, and outcomes. This narrative review is designed to summarize current evidence regarding the urobiome and explore its diagnostic and therapeutic potential. Methods: Studies between 2019 and 2024 were identified through the PubMed/MEDLINE and Google Scholar databases. Case reports and non-English-language articles were excluded. Results: The main findings revealed that specific bacteria, viruses, and taxa are linked to bladder cancer presence, progression, and response to immunotherapy treatment. Urinary microbiota differ by tumor type, sex, smoking status, and occupational exposure to toxins. Conclusions: Urinary microbiome and certain types of viruses present in urine may serve as promising tools to enhance bladder cancer diagnosis and predict treatment response. However, larger longitudinal studies are needed to confirm and establish these findings. Furthermore, integration of the urinary microbiome in clinical practice and public health strategies may reduce disease-related burden.	bladder
Intermediate-risk Non-muscle-invasive Bladder Cancer: Recommendations for Definitions, Risk Stratification, Management Strategies, and Clinical Trial Design from the International Bladder Cancer Group.	BACKGROUND AND OBJECTIVE: Intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease, and standardized definitions and risk-guided management are critical for appropriate patient care and clinical trial development. METHODS: A global committee of bladder cancer experts developed IR-NMIBC recommendations. Working groups reviewed literature and drafted recommendations, which were voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During an August 2024 meeting, voting results and evidence were presented, and recommendations were refined. Final recommendations achieved >75% agreement. KEY FINDINGS AND LIMITATIONS: The IBCG recommends inclusion of only low-grade (LG; G1 and G2) tumors in the IR-NMIBC category, risk stratified using the IBCG IR-NMIBC risk scoring system. Given the relatively indolent course and treatment burden of IR-NMIBC, therapeutic deintensification with active surveillance or office-based ablation is appropriate for select patients. Morbidity related to transurethral resection of a bladder tumor can be mitigated by forgoing restaging resection in completely resected LG tumors and not mandating muscularis propria sampling. Perioperative chemotherapy reduces recurrences, and additional adjuvant intravesical treatment should be risk stratified. Clinical trials evaluating novel IR-NMIBC therapies, including adjuvant and ablative designs, should incorporate patient-reported outcomes and risk-stratified controls. Ablative trials, as proof-of-concept studies for efficacy, require randomized controlled studies in the adjuvant setting to confirm superiority over the standard of care. CONCLUSIONS AND CLINICAL IMPLICATIONS: The IBCG consensus recommendations provide practical guidance for clinical care and clinical trial design for patients with IR-NMIBC.	bladder